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A Role for Immune Tolerance in Pediatric Acute Lymphoblastic Leukemia (ALL)

Researchers at the Center for Childhood Cancer Research, including Alix E. Seif, MD, MPH, have developed a unique mouse model system to develop new strategies to induce immune-mediated protection against ALL disease progression.

Recent developments in engineered T cells (CAR Ts) or bispecific antibodies (BiTEs) that recognize specific leukemia antigens show tremendous clinical promise. Unfortunately, some patients experience relapses when the engineered immune cells or antibodies no longer persist, showing that the immune system itself is not developing immune “memory” for the leukemia. Furthermore, some patients relapse when the leukemia is able to alter or stop expressing the targeted antigen, suggesting that immune recognition of multiple antigens might be more effective.

The Seif Laboratory has developed a model system consisting of B cell precursor ALL cell lines derived from leukemic transgenic mice. The cell lines contain a lentiviral construct that encodes green fluorescent protein (GFP) in tandem with bioluminescent firefly luciferase (luc).

The GFP/luc signals serve a dual purpose: they act as potent neoantigens capable of stimulating leukemia-specific immune responses and a bioluminescent reporter for the highly sensitive detection of minimal residual disease (MRD).

In this model, GFP/luc cells were able to engraft and expand in normal mice but were subsequently eliminated by a T cell-dependent immune response against the neoantigen. The remission induced by the T cell immunoprotective response provided long term immunological memory against ALL.

Furthermore, this model system induces immune recognition of leukemia-associated antigens beyond GFP/luc. Mice who were able to reject the GFP/luc-modified leukemia are also able to reject unmodified leukemia, showing that their immune systems are able to recognize multiple tumor antigens. Importantly, this ability is lost in mice who are tolerant to GFP/luc or other leukemia-associated antigens. These findings suggested that pre-existing immune tolerance to leukemia-associated antigens might play a role in undermining immune responses in patients with ALL.

Additional studies are currently underway to identify methods that can be used to break immune tolerance to leukemia-associated antigens and better control MRD in pediatric ALL.